Abstract I am seeking an R35 to address the fundamental issue of how right and left shifts in the O2 hemoglobin dissociation curve influence oxygen transport in humans. I am also proposing to translate key findings to the treatment of diseases with specific defects in the O2 transport cascade like idiopathic pulmonary fibrosis and/or congestive heart failure. I am also proposing reverse translation from observations in patients to more basic studies on O2 delivery and mitochondrial function. Hemoglobin is one of the sentinel molecules responsible for the concept of ?molecular medicine?. A central element of this paradigm is that when the properties of the foundational molecular components of a system are understood, then more complex systems phenomenon will be explained. However, ?well-established? concepts about hemoglobin and whole body oxygen transport are contradictory and deserve further scrutiny. The standard teaching is that in response to hypoxia, there is an acute right shift in the O2 hemoglobin dissociation curve via the actions of 2,3-DPG. This right shift facilitates the off-loading of oxygen at the tissues and protects against tissue hypoxia. However, species adapted to high altitude via evolution have left shifted O2 hemoglobin dissociation curves. This suggests that during hypoxia, loading more oxygen at the lung and relying on low tissue PO2 to maintain oxygen transport is a better overall solution to the challenge of hypoxia. These divergent observations indicate there is a complex set of context-dependent physiological ?trade-offs? associated with shifts in O2 hemoglobin dissociation curve and O2 delivery. In this application, I propose studying patients at the Mayo Clinic with rare right and left shifted hemoglobin variants as unique ?experiments in nature? that will allow exploration of these trade-offs. Patient studies will be augmented with studies in healthy volunteers using repurposed drugs that cause right and left shifts of the O2 hemoglobin dissociation curve. Insight from these studies will then be translated to clinical populations. If tissue oxygenation is maintained in humans with left shifted curves, then drugs that cause a left shift might be useful in patients with pulmonary diffusion limitation. This would permit such patients to better oxygenate their blood at the lung with a lower FiO2 and reduced work of breathing. Likewise, there is chronic tissue hypoxia in congestive heart failure that might be reduced by drugs that cause a right shift in the O2 hemoglobin dissociation curve. These changes in O2 delivery might also evoke long term changes in muscle mitochondrial function that will suggest follow-up reverse translation mechanistic studies. Importantly, I am uniquely qualified to explore these ideas because of my: 1) access to unique patients, 2) experience in drug re-purposing, 3) expertise in cardiorespiratory physiology, and 4) technical ability to measure essentially every element of the O2 transport cascade in humans. Finally, because the R35 mechanism is designed to promote flexibility and risk taking by the PI, it is ideal to pursue this big issue and the bi-directional translational opportunities that will flow from the experimental approach I have proposed.